Differential role for p120-catenin in regulation of TLR4 signaling in macrophages.

Yang Z, Sun D, Yan Z, Reynolds AB, Christman JW, Minshall RD, Malik AB, Zhang Y, Hu G
J Immunol. 2014 193 (4): 1931-41

PMID: 25015829 · PMCID: PMC4119481 · DOI:10.4049/jimmunol.1302863

Activation of TLR signaling through recognition of pathogen-associated molecular patterns is essential for the innate immune response against bacterial and viral infections. We have shown that p120-catenin (p120) suppresses TLR4-mediated NF-кB signaling in LPS-challenged endothelial cells. In this article, we report that p120 differentially regulates LPS/TLR4 signaling in mouse bone marrow-derived macrophages. We observed that p120 inhibited MyD88-dependent NF-κB activation and release of TNF-α and IL-6, but enhanced TIR domain-containing adapter-inducing IFN-β-dependent IFN regulatory factor 3 activation and release of IFN-β upon LPS exposure. p120 silencing diminished LPS-induced TLR4 internalization, whereas genetic and pharmacological inhibition of RhoA GTPase rescued the decrease in endocytosis of TLR4 and TLR4-MyD88 signaling, and reversed the increase in TLR4-TIR domain-containing adapter-inducing IFN-β signaling induced by p120 depletion. Furthermore, we demonstrated that altered p120 expression in macrophages regulates the inflammatory phenotype of LPS-induced acute lung injury. These results indicate that p120 functions as a differential regulator of TLR4 signaling pathways by facilitating TLR4 endocytic trafficking in macrophages, and support a novel role for p120 in influencing the macrophages in the lung inflammatory response to endotoxin.

Copyright © 2014 by The American Association of Immunologists, Inc.

MeSH Terms (27)

Acute Lung Injury Adaptor Proteins, Vesicular Transport Animals Bronchoalveolar Lavage Fluid Catenins Cells, Cultured Endocytosis Interferon-beta Interferon Regulatory Factor-3 Interleukin-6 Leukocyte Count Lipopolysaccharides Macrophages, Alveolar Male Mice Mice, Inbred C57BL Myeloid Differentiation Factor 88 Neutrophils NF-kappa B Protein Transport rhoA GTP-Binding Protein RNA Interference Signal Transduction Toll-Like Receptor 2 Toll-Like Receptor 3 Toll-Like Receptor 4 Tumor Necrosis Factor-alpha

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